The present invention relates to novel oil-in-water emulsion pharmaceutical composition containing 2,6-diisopropylphenol, i.e. propofol.
Propofol is an injectable anesthetic which can be used to induce and maintain general anesthesia and for sedation, for example in intensive care units. There are a number of known propofol formulations. See, for example, UK Patent 1472793, U.S. Pat. Nos. 4,452,817 and 5,714,520. One formulation of propofol is an oil-in-water emulsion.
Sterile propofol formulations, including oil-in-water emulsion formulations of propofol, have been taught to include preservatives to prevent extrinsic contamination. Ideally, the concentration of preservative is kept to a minimum, especially where propofol is administered for the maintenance of general anaesthesia and sedation where such treatment allows for the possibility of significant amounts of preservative being administered to a patient over the course of treatment. In addition, to be effective for the intended purpose, namely the prevention of extrinsic contamination, a preservative should be broad spectrum, i.e. effective against gram negative (such as Pseudomonas aeruginosa) and gram positive (such as Staphylococcus aureus) bacteria as well as yeast (such as Candida albicans) at useful concentrations. Edetate has been taught to be the only preservative which has broad spectrum antimicrobial effect and can be exerted in the aqueous phase without destabilizing the oil-in-water propofol formulation. See, U.S. Pat. No. 5,714,520.
Tromethamine (TRIS) is a known buffering agent and electrolyte. It has also been previously suggested that tromethamine may enhance the antimicrobial effects of EDTA and other agents. Tjoelker, et al., J. Dairy Science, 68, Suppl. 1, 196 (1985); Angus Chemical Company, Technology Review, p. 10-13. Tromethamine has not been taught to be effective alone as an antimicrobial agent. Furthermore, due to its ionic nature, tromethamine would not be expected to be compatible with an oil-in-water emulsion because ionic compounds and electrolytes are known to destabilize oil-in-water emulsions. See, U.S. Pat. No. 5,714,520.
Despite these and other teachings, it has surprisingly been found that tromethamine is useful as a preservative in an oil-in-water emulsion. Thus, compositions of the present invention are excellent broad spectrum preservatives useful in an oil-in-water emulsion containing propofol.